We are requesting funds for the second competitive renewal of our Program Project Grant (PPG) from NIDA, entitled: Molecular Neurobiology of Drug Addiction. The PPG supports a series of highly interactive and multidisciplinary studies aimed at delineating the molecular and cellular mechanisms underlying opiate and cocaine addiction. Each research area represents an integration of molecular, biochemical, electrophysiological, neuropharmacological, neuroanatomical, and behavioral levels of analysis. The PPG is organized into two scientific Cores, and five Projects. The Transgenic Core (PI, Eric Nestler) is responsible for breeding the many lines of transgenic and knockout mice, and for constructs for viral-mediated gene transfer, to be utilized in the proposed research. The Core is also responsible for the construction of several new lines of mutant mice, including those with inducible tissue-specific transgenes and knockouts. The Behavioral Core (PI, David Self) is responsible for providing to individual Projects a broad battery of relatively routine behavioral tests in mice and rats relevant to drug abuse and addiction. In addition, conditioned reward and intracranial self-stimulation paradigms are available via subcontracts with Yale (Jane Taylor) and Harvard (Bill Carlezon), respectively. Project 1 (PI, Eric Nestler) is a continuation of a productive and collaborative effort among several laboratories to study the molecular and cellular mechanisms by which opiates regulate locus coeruleus neurons, and to explore neuronal types in brain that show similar adaptations. Project 2 (PI, Rob Malenka via a Stanford subcontract) is newly reconfigured, and focuses on characterizing the functional consequences of specific drug-induced molecular adaptations in the mesolimbic dopamine system in neurophysiology and synaptic plasticity models. Project 3 (PIs, Ralph DiLeone; and Ron Duman via a Yale subcontract) is a continuation of collaborative molecular, cellular, and behavioral studies of the role of hypothalamic feeding peptides in drug addiction. Project 4 (PI, David Self) is a continuation of efforts to study the role of drug-induced molecular adaptations in the mesolimbic dopamine system in animal models of drug reinforcement and craving. Project 5 (PI, Steve Gold) is a new effort to examine the influence of RGS proteins, which modulate G protein signaling, at the level of the mesolimbic dopamine system, on drug abuse and addiction. Together, the proposed program of research promises to contribute to a better understanding of drug addiction at the molecular, cellular, and systems levels.